Children born small for gestational age may demonstrate continued growth retardation, resulting in persistent short stature. In the majority of the cases, this is linked with abnormal growth hormone secretion and also abnormal insulin-like growth factor levels. This review discusses the treatment of such children with recombinant human growth hormone. It illustrates the importance of starting therapy early, the dose-dependent response, and the advantages of continuous therapy and describes safety considerations.

Keywords:
Recombinant human growth hormone therapy, Safety considerations, growth hormone therapy, Small-for-gestational-age children
1.
de Zegher F, Francois I, Van Helvoit M, Beckers D, Ibáñez L, Chatelain P: Growth hormone treatment of short children born small for gestational age. Trends Endocrinol Metab 1998;9:233–237.
2.
Lee PA, Chernausek SD, Hokken-Koelega AC, Czernichow P; International Small for Gestational Age Advisory Board: International Small for Gestational Age Advisory Board consensus development conference statement: management of short children born small for gestational age, April 24–October 1, 2001. Pediatrics 2003;111(6 Pt 1): 1253–1261.
3.
Clayton PE, Cianfarani S, Czernichow P, Johannsson G, Rapaport R, Rogol A: Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab 2007;92:804–810.
4.
Martin JA, Hamilton BE, Ventura SJ, Menacker F, Park MM: Births: final data for 2000. Natl Vital Stat Rep 2002;50:1–101.
5.
Hediger ML, Overpeck MD, Maurer KR, Kuczmarski RJ, McGlynn A, Davis WW: Growth of infants and young children born small or large for gestational age: findings from the Third National Health and Nutrition Examination Survey. Arch Pediatr Adolesc Med 1998;152:1225–1231.
6.
Usher R, McLean F: Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr 1969;74:901–910.
7.
Lee PA, Blizzard RM, Cheek DB, Holt AB: Growth and body composition in intrauterine growth retardation (IUGR) before and during human growth hormone administration. Metabolism 1974;23:913–919.
8.
Chatelain P, Job JC, Blanchard J, Ducret JP, Oliver M, Sagnard L, Vanderschueren-Lodeweyckx M: Dose-dependent catch-up growth after 2 years of growth hormone treatment in intrauterine growth-retarded children. Belgian and French Pediatric Clinics and Sanofi-Choay (France). J Clin Endocrinol Metab 1994;78:1454–1460.
9.
Boersma B, Wit JM: Catch-up growth. Endocr Rev 1997;18:646–661.
10.
Hokken-Koelega AC, De Ridder MA, Lemmen RJ, Den Hartog H, de Muinck Keizer-Schrama SM, Drop SL: Children born small for gestational age: do they catch up? Pediatr Res 1995;38:267–271.
11.
Karlberg J, Albertsson-Wikland K: Growth in full-term small-for-gestational-age infants: from birth to final height. Pediatr Res 1995;38:733–739.
12.
Leger J, Levy-Marchal C, Bloch J, Pinet A, Chevenne D, Porquet D, Collin D, Czernichow P: Reduced final height and indications for insulin resistance in 20 year olds born small for gestational age: regional cohort study. BMJ 1997;315:341–347.
13.
Carel JC, Chatelain P, Rochiccioli P, Chaussain JL: Improvement in adult height after growth hormone treatment in adolescents with short stature born small for gestational age: results of a randomized controlled study. J Clin Endocrinol Metab 2003;88:1587–1593.
14.
Jaquet D, Collin D, Levy-Marchal C, Czernichow P: Adult height distribution in subjects born small for gestational age. Horm Res 2004;62:92–96.
15.
Gluckman PD: Clinical review 68: the endocrine regulation of fetal growth in late gestation: the role of insulin-like growth factors. J Clin Endocrinol Metab 1995;80:1047–1050.
16.
Le Roith D: Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors. N Engl J Med 1997;336:633–640.
17.
DeChiara TM, Efstratiadis A, Robertson EJ: A growth deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature 1990;345:78–80.
18.
Deiber M, Chatelain P, Naville D, Putet G, Salle B: Functional hypersomatotropism in small for gestational age (SGA) newborn infants. J Clin Endocrinol Metab 1989;68:232–234.
19.
de Waal WJ, Hokken-Koelega AC, Stijnen T, de Muinck Keizer-Schrama SM, Drop SL: Endogenous and stimulated GH secretion, urinary GH excretion, and plasma IGF-I and IGF-II levels in prepubertal children with short stature after intrauterine growth retardation. The Dutch Working Group on Growth Hormone. Clin Endocrinol (Oxf) 1994;41:621–630.
20.
Boguszewski M, Bjarnason R, Jansson C, Rosberg S, Albertsson-Wikland K: Hormonal status of short children born small for gestational age. Acta Paediatr Suppl 1997;423:189–192.
21.
Albertsson-Wikland K: Growth hormone secretion and growth hormone treatment in children with intrauterine growth retardation. Swedish Paediatric Study Group for Growth Hormone Treatment. Acta Paediatr Scand Suppl 1989;349:35–41, discussion 53–54.
22.
Boguszewski M, Jansson C, Rosberg S, Albertsson-Wikland K: Changes in serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 levels during growth hormone treatment in prepubertal short children born small for gestational age. J Clin Endocrinol Metab 1996;81:3902–3908.
23.
Sas T, de Waal W, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega AC: Growth hormone treatment in children with short stature born small for gestational age: 5-year results of a randomized, double-blind, dose-response trial. J Clin Endocrinol Metab 1999;84:3064–3070.
24.
Curhan GC, Willett WC, Rimm EB, Spiegelman D, Ascherio AL, Stampfer MJ: Birth weight and adult hypertension, diabetes mellitus, and obesity in US men. Circulation 1996;94:3246–3250.
25.
Ong KK, Dunger DB: Perinatal growth failure: the road to obesity, insulin resistance and cardiovascular disease in adults. Best Pract Res Clin Endocrinol Metab 2002;16:191–207.
26.
Yarbrough DE, Barrett-Connor E, Kritz-Silverstein D, Wingard DL: Birth weight, adult weight, and girth as predictors of the metabolic syndrome in postmenopausal women: the Rancho Bernardo Study. Diabetes Care 1998;21:1652–1658.
27.
Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM: Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 1993;36:62–67.
28.
Hofman PL, Cutfield WS, Robinson EM, Bergman RN, Menon RK, Sperling MA, Gluckman PD: Insulin resistance in short children with intrauterine growth retardation. J Clin Endocrinol Metab 1997;82:402–406.
29.
Stabler B, Siegel PT, Clopper RR, Stoppani CE, Compton PG, Underwood LE: Behavior change after growth hormone treatment of children with short stature. J Pediatr 1998;133:366–373.
30.
Kranzler JH, Rosenbloom AL, Proctor B, Diamond FB Jr, Watson M: Is short stature a handicap? A comparison of the psychosocial functioning of referred and nonreferred children with normal short stature and children with normal stature. J Pediatr 2000;136:96–102.
31.
McCarton CM, Wallace IF, Divon M, Vaughan HG Jr: Cognitive and neurologic development of the premature, small for gestational age infant through age 6: comparison by birth weight and gestational age. Pediatrics 1996;98:1167–1178.
32.
Paz I, Gale R, Laor A, Danon YL, Stevenson DK, Seidman DS: The cognitive outcome of full-term small for gestational age infants at late adolescence. Obstet Gynecol 1995;85:452–456.
33.
Larroque B, Bertrais S, Czernichow P, Leger J: School difficulties in 20-year-olds who were born small for gestational age at term in a regional cohort study. Pediatrics 2001;108:111–115.
34.
Lundgren EM, Cnattingius S, Jonsson B, Tuvemo T: Intellectual and psychological performance in males born small for gestational age with and without catch-up growth. Pediatr Res 2001;50:91–96.
35.
Puga B, Ferrández Longás A, García Romero R, Mayayo E, Labarta JI: Psychomotor and intellectual development of children born with intrauterine growth retardation (IUGR). J Pediatr Endocrinol Metab 2004;17(Suppl 3):457–462.
36.
van Pareren YK, Duivenvoorden HJ, Slijper FS, Koot HM, Hokken-Koelega AC: Intelligence and psychosocial functioning during long-term growth hormone therapy in children born small for gestational age. J Clin Endocrinol Metab 2004;89:5295–5302.
37.
Ranke MB, Lindberg A: Growth hormone treatment of short children born small for gestational age or with Silver-Russell syndrome: results from KIGS (Kabi International Growth Study), including the first report on final height. Acta Paediatr Suppl 1996;417:18–26.
38.
van Pareren YK, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega AC: Effect of discontinuation of growth hormone treatment on risk factors for cardiovascular disease in adolescents born small for gestational age. J Clin Endocrinol Metab 2003;88:347–353.
39.
Cutfield WS, Wilton P, Bennmarker H, Albertsson-Wikland K, Chatelain P, Ranke MB, Price DA: Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth hormone treatment. Lancet 2000;355:610–613.
40.
Czernichow P: Growth hormone treatment strategy for short children born small for gestational age. Horm Res 2004;62(Suppl 3): 137–140.
41.
de Zegher F, Albertsson-Wikland K, Wollmann HA, Chatelain P, Chaussain JL, Löfström A, Jonsson B, Rosenfeld RG: Growth hormone treatment of short children born small for gestational age: growth responses with continuous and discontinuous regimens over 6 years. J Clin Endocrinol Metab 2000;85:2816–2821.
42.
de Zegher F, Hokken-Koelega A: Growth hormone therapy for children born small for gestational age: height gain is less dose dependent over the long term than over the short term. Pediatrics 2005;115:458–462.
43.
Brook C: Short stature; in Brook CG (ed): Clinical Paediatric Endocrinology. Oxford, Blackwell, 1995.
44.
Reiter EO, Rosenfeld RG: Normal and aberrant growth; in Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds): Williams Textbook of Endocrinology. Philadelphia, Saunders, 1998, pp 1427–1507.
45.
Rapaport R: Growth and growth hormone in children born small for gestational age. Growth Horm IGF Res 2004;14(Suppl A):S3–S6.
46.
Ranke MB, Lindberg A, Cowell CT, Wikland KA, Reiter EO, Wilton P, Price DA; KIGS International Board: Prediction of response to growth hormone treatment in short children born small for gestational age: analysis of data from KIGS (Pharmacia International Growth Database). J Clin Endocrinol Metab 2003;88:125–131.
47.
Bozzola E, Lauriola S, Messina MF, Bona G, Tinelli C, Tato L: Effect of different growth hormone dosages on the growth velocity in children born small for gestational age. Horm Res 2004;61:98–102.
48.
van Pareren YK, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega AC: Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial. J Clin Endocrinol Metab 2003;88:3584–3590.
49.
Hokken-Koelega AC, de Waal WJ, Sas TC, van Pareren YK, Arends NJ: Small for gestational age (SGA): endocrine and metabolic consequences and effects of growth hormone treatment. J Pediatr Endocrinol Metab 2004;17(Suppl 3):463–469.
50.
Boguszewski M, Albertsson-Wikland K, Aronsson S, Gustafsson J, Hagenäs L, Westgren U, Westphal O, Lipsanen-Nyman M, Sipilä I, Gellert P, Müller J, Madsen B: Growth hormone treatment of short children born small-for-gestational-age: the Nordic Multicentre Trial. Acta Paediatr 1998;87:257–263.
51.
Simon D, LegerJ, Fjellestad-PaulsenA, Crabbé R, Czernichow P; SGA Study Group: Intermittent recombinant growth hormone treatment in short children born small for gestational age: 4-year results of a randomized trial of two different treatment regimens. Horm Res 2006;66:118–123.
52.
Fjellestad-Paulsen A, Simon D, Czernichow P: Short children born small for gestational age and treated with growth hormone for three years have an important catch-down five years after discontinuation of treatment. J Clin Endocrinol Metab 2004;89:1234–1239.
53.
Dos Santos C, Essioux L, Teinturier C, Tauber M, Goffin V, Bougnères P: A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat Genet 2004;36:720–724.
54.
Le Stunff C, Fallin D, Schork NJ, Bougnères P: The insulin gene VNTR is associated with fasting insulin levels and development of juvenile obesity. Nat Genet 2000;26:444–446.
55.
Leger J, Carel C, Legrand I, Paulsen A, Hassan M, Czernichow P: Magnetic resonance imaging evaluation of adipose tissue and muscle tissue mass in children with growth hormone (GH) deficiency, Turner’s syndrome, and intrauterine growth retardation during the first year of treatment with GH. J Clin Endocrinol Metab 1994;78:904–909.
56.
Pollak M: Insulin-like growth factor physiology and neoplasia. Growth Horm IGF Res 2000;10(Suppl A):S6–S7.
57.
Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, Stampfer MJ: Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst 1999;91:620–625.
58.
Baxter RC, Butt AJ, Schedlich LJ, Martin JL: Antiproliferative and pro-apoptotic activities of insulin-like growth factor-binding protein-3. Growth Horm IGF Res 2000;10(Suppl A):S10–S11.
59.
Martin JL, Baxter RC: Oncogenic ras causes resistance to the growth inhibitor insulin-like growth factor binding protein-3 (IGFBP-3) in breast cancer cells. J Biol Chem 1999;274:16407–16411.
60.
Tuffli GA, Johanson A, Rundle AC, Allen DB: Lack of increased risk for extracranial, nonleukemic neoplasms in recipients of recombinant deoxyribonucleic acid growth hormone. J Clin Endocrinol Metab 1995;80:1416–1422.
61.
Allen DB, Rundle AC, Graves DA, Blethen SL: Risk of leukemia in children treated with human growth hormone: review and reanalysis. J Pediatr 1997;131(1 Pt 2):S32–S36.
62.
Howell SJ, Wilton P, Lindberg A, Shalet SM: Growth hormone replacement and the risk of malignancy in children with neurofibromatosis. J Pediatr 1998;133:201–205.
63.
Price DA, Wilton P, Jonsson P, Albertsson-Wikland K, Chatelain P, Cutfield W, Ranke MB: Efficacy and safety of growth hormone treatment in children with prior craniopharyngioma: an analysis of the Pharmacia and Upjohn International Growth Database (KIGS) from 1988 to 1996. Horm Res 1998;49:91–97.
© 2007 S. Karger AG, Basel
2007
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.